The development of an effective AIDS vaccine is in urgent need for the control of the rapid spread of HIV infection. The focus of this project is to explore novel vaccine design strategies for eliciting cross-reactive beutralizing antibody responses against HIV. The Env protein of HIV is synthesized as an Gp160 precursor and processed into the surface subunit (SU) Gp120 and the transmembrane subunit (TM) Gp41. The SU protein mediates interaction with the receptor molecule CD4 as well as co-receptor molecules such as CCR5 and CXCR4, while the TM protein anchors the envelope glycoprotein on viral or cell membranes and mediates fusion between viral and cellular membranes for virus entry. It has been shown that the TM protein contains conserved neutralizing epitopes. In this study, we plan to construct novel chimeric proteins between the influenza hemmagglutini (HA) and the HIV TM protein (Gp41) and investigate whether such chimeric proteins will be advantageous in eliciting neutralizing antibodies against the HIV envelope protein. Specifically, we will first construct a series of chimeric protein and characterize their surface expression as well as reactivity of antibodies directed against the HIV TM protein. We will then evaluate immunogenicities of the candidate chimeric proteins in small laboratory models (mice and guinea pigs) in the context of DNA immunization or VLP immunization. We will also test the effectiveness of different priming-boosting protocols in eliciting cross-reactive neutralizing antibodies against HIV. [unreadable] [unreadable]